1. Field of the Invention
The present invention relates generally to the fields of immunology, transplantation, graft rejection, and immunotolerance. More particularly, it concerns the use of collagen compounds to down regulate immune responses to such as those that result in allograft rejection.
2. Description of Related Art
Transplantation protocols are well-accepted in the medical community. For example, lung transplantation is a therapeutic modality for the treatment of many end stage pulmonary diseases. However, transplant rejection occurs more often in the lung as compared to other solid organ allografts. The leading cause of death in lung allograft recipients is chronic rejection, known as bronchiolitis obliterans (BO) (Trulock, 1997; Westra et al., 1990). The pathogenesis of chronic rejection is poorly understood; however the risk of developing chronic rejection is believed to be related with repeated acute rejection episodes.
Rejection of allografts is presently understood to be initiated by the recognition of allogeneic (i.e. donor) major histocompatibility complex (MHC) molecules by recipient/host T-lymphocytes leading to upregulated cellular and humoral immunity (Sayagh et al., 1994). The MHC antigens are typically presented to the recipient T-lymphocytes by antigen presenting cells (APC's ), such as macrophages and dendritic cells. (Trulock, 1997; Heidler et al. 2000). Although immunosuppressive compounds may be used in an attempt to modulate rejection, immunosuppressive agents often fail to prevent continued rejection episodes. Thus, other methods for inducing indefinite acceptance of the allograft, also known as induction of immunological tolerance, are sought.
Allogeneic MHC molecules are the stimulus and target of the immune response during rejection. Therefore, MHC-derived peptides or synthetic peptides that may be homologous to MHC antigens have been the focus of investigations attempting to induce immunological tolerance to allografts (Krensky and Clayberger, 1997; Oluwole et al., 1993). In addition, a very recent study reports the induction of tolerance to multiple allogeneic MHC molecules in vitro by a non-polymorphic synthetic peptide derived from MHC molecules (Murphy et al., 1999). However, none of these reports appear to have resolved the issues of allograft rejection, and, in particular lung allograft rejection.
Since recognition of polymorphic regions of donor MHC molecules is usually the stimulus for allo-immune responses, immunological tolerance induced by peptides derived from the donor MHC is often specific to the allele of the donor MHC molecules. Therefore, identification of proteins/peptides that are highly conserved amongst individuals and induce immunologic tolerance across multiple MHC alleles may be of great benefit for the allograft recipient. However, the use of such proteins/peptides for induction of immunological tolerance to lung allografts has not been evaluated. Further, no proteins/peptides that are useful for such tolerance have yet been identified.
Further, despite the existence of different techniques to induce tolerance to solid organ allografts, such as donor specific blood transfusion, thymic injection with donor-derived APC's, or systemic immunization with peptides derived from donor MHC molecules prior to transplantation (Krensky and Clayberger, 1997), for any of these techniques to be effective the specific donor MHC molecules must be known several weeks prior to transplantation to allow sufficient time, i.e., weeks to months, for tolerance induction to occur. However, in the typical scenario only a few hours exist between the identification of a potential donor and the transplantation surgery, and therefore, time is not available for tolerance induction by these techniques.
Thus, there is acute need for developing methods that can induce tolerance to any possible donor tissue, irrespective of the MHC-type, prior to the identification of a suitable transplant donor.